DiscoveryBioMed, Inc. (DBM) has launched an innovative and automation-friendly drug discovery program to screen synthetic organic small molecule collections on differentiated human adipocyte platforms to discover a new class of therapeutic drugs for type 2 diabetes mellitus (T2DM) and obesity. Differentiated human adipocytes from visceral (central abdominal depot) origin are challenged with test compounds to discover hit small molecules that trigger the secretion of endogenous adiponectin. Adiponectin is an established biomarker and causative mediator in obesity-related diseases. Plasma concentrations of this adipokine are reduced in vivo in obese and diabetic patients. Accordingly, up-regulating endogenous adiponectin expression and secretion has been proposed as a high-priority therapeutic strategy for obesity-related diseases. The ultimate goal of this work is to develop, optimize, validate and implement the human fat cell-driven drug discovery platform based on immortalized and primary human visceral adipocytes to discover novel adiponectin secretagogues for obesity, diabetes and related metabolic diseases as well as ailments that arise from secondary complications of metabolic disease. The key ingredient in this program is DBM's core principle of using biologically- and disease-relevant human cellular platforms to 'de-risk' de novo drug discovery programs. This core principle reflects DBM's unique angle, approach and offering to the drug discovery space. Primary and immortal human pre-adipocytes from normal donors and type 2 diabetes mellitus patients are differentiated by a patent-protected process that employs a novel differentiation medium. It is DBM's view that successful de novo drug discovery programs must utilize a disease-relevant human cell platform and a disease-relevant target/phenotypic endpoint (i.e. human adipocytes secreting human adiponectin). Obesity and obesity-related diseases including T2DM, atherosclerosis, cardiovascular disease, fatty liver disease, and diabetic hyperglycemic injury of the eye, heart, kidney and peripheral nerves have reached epidemic proportions in the US and the developed world and exact huge morbidity and cost burdens on society. An enormous unmet clinical need exists for new therapeutic drugs to combat these diseases, especially in Alabama where DBM resides in the heart of the Southeastern Diabetes Belt. Drug pipelines for metabolic diseases are in peril, with most pipeline drugs for obesity-related diseases simply re-branded, re-purposed or combined because of an undefined weight loss side effect. Many of these new or re-purposed drug classes for metabolic diseases have failed and been abandoned recently. There is dire need and window of opportunity to re-kindle the metabolic diseases drug discovery effort with novel and innovative programs. DBM rises to that unmet need with the following major project milestones that: (1) Establish a robust differentiated human visceral adipocyte drug discovery platform; (2) Design, optimize and implement a primary de novo drug discovery HTS-friendly bioassay; (3) Screen the 60,000 synthetic organic compounds within the DBM molecular library to discover novel endogenous adiponectin secretagogues; (4) Validate putative hits from the primary HTS bioassay with a robust Critical Path; and (5) Perform chemoinformatics on the validated hit compounds to identify hit-to-lead chemical classes worthy of deeper assessment and profiling. DBM is already 10% of the way to this screening goal and has already performed validation and chemoinformatics on the early output from our Critical Path. DBM seeks SBIR funds to deepen and accelerate this critical metabolic diseases drug discovery program.